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The U.S. Food and Drug Administration on February 23, 2026 issued draft guidance for sponsors seeking approval for targeted individualized therapies by generating substantial evidence of effectiveness and safety when randomized controlled trials are not feasible due to small patient populations.
The draft guidance, issued by the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER), specifically discusses genome editing and RNA-based therapies such as antisense oligonucleotides, while leaving open the possibility that the framework may apply to additional tailored therapeutics provided they directly address the underlying specific cause of the disease.
“President Trump promised to accelerate cures for American families — and we are delivering, especially for children with ultra-rare diseases who cannot afford to wait,” said Health and Human Services Secretary Robert F. Kennedy, Jr. In a press briefing, he described the burden families face when approvals take years: “There are not enough patients. The approval will take too long. You just have to wait for the science to catch up with your child.” Kennedy added, “A disease with a hundred distinct mutations in the same gene will no longer require 100 clinical trials. When biology is clear and the science is sound, we will evaluate therapies based upon strong evidence and not arbitrary barriers. Individualized medicine is no longer theoretical.”
FDA Commissioner Marty Makary added, “This guidance is a critical step the FDA is taking to tailor our regulatory approach to patients with ultra-rare conditions” . “It turns out rare diseases are pretty common. 30 million Americans have a rare disease. That’s one in 11 in our country.” Makary said, “Historically, rare diseases have been, at the FDA, an afterthought.”
The draft guidance focuses on therapies that target a specific genetic, cellular, or molecular abnormality and are designed to correct or modify the underlying cause of disease. To qualify, sponsors are expected to identify the disease-causing abnormality and demonstrate that the therapy targets either the root cause or a proximate biological pathway. The FDA also expects sponsors to rely on well-characterized natural history data in untreated patients and to confirm successful target drugging or editing.
Because genome editing technologies are designed to be highly specific to unique DNA sequences, a product targeting different mutations in a single gene could be included in a single product application and potentially evaluated through the use of master protocols that evaluate these product variations in a single trial. A highly supported “plausible mechanism” of action may then be used to support the addition of other such genome editing product variants intended to treat patients with mutations that were not included in the clinical trial used to support the original application.
“What is a plausible mechanism pathway? It’s common sense,” Makary said.
The FDA recognizes that an adequate and well-controlled clinical investigation in this context will often include a small sample size; therefore, investigation results should be sufficiently robust to help exclude chance findings. When determining effectiveness, the FDA considers the specific disease, the strength of the evidence, and the challenges of conducting clinical investigations for individualized therapies. Kennedy said, “To the doctors here, bring us rigorous science. Define clear endpoints. Collect strong data. Move with discipline and speed and we will move with you.”
Source: FDA
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